Characterization Of The Biophysical Impact Of Rigid Red Blood Cells In Sickle Cell Disease: Creating A Novel Path For Treatment

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Sickle cell disease (SCD) is a hereditary blood disease affecting approximately 100,000 Americans and millions more worldwide. Patients with SCD have a significantly shortened lifespan with a compromised quality of life since childhood, i.e., frequent hospitalization for acute pain crises, infections, acute breathing problems and strokes. Current treatment strategies are limited and highly invasive, e.g., addictive narcotics(opiods) and blood transfusions. The most visible indicators of SCD are changes in the patient's red blood cells (RBCs), which become more rigid and are often deformed from their normal round shape to a crescent ("sickle") shape. Though these changes are well known, little is known about how the blood flow alterations created solely by rigid RBCs impact the functionality of other blood cells, particularly white blood cells (WBCs) and platelets, which play an important role in disease symptoms such as infections and acute pain. Thus, this project seeks to develop a unique combination of experimental tools to quantify how RBC rigidity causes the altered WBC and platelet interactions that lead to the high rate of infection, blood clotting and pain crisis associated with SCD. Insights gained are expected to lead to better treatments aimed at reducing the number of crisis episodes, infection, hospital days, and most importantly, need for opioids. The project involves multi-disciplinary activities in biology and engineering that create excellent educational and research opportunities in STEM areas, showcasing the vast opportunities that exist for basic science and engineering to impact the treatment of human diseases. The research findings will be disseminated to a broad audience, from K-12 to undergraduate and graduate levels, and the research team will provide education to SCD patients and families during the consent process regarding the importance of research in sickle cell, local advocacy, and how patients can be involved in their care.Though rigid sickle shaped RBCs (irreversible i-sRBCs) are the hallmark of SCD, only a small fraction of these cells is present in the patient's bloodstream at a given time due to their high rate of lysing. Instead, the highly rigid, but not sickle-shaped cells (reversible r-RBCs) represent the main sickled RBCs circulating in SCD. However, little attention has been given to how the persistent presence of the r-sRBCs in the bloodstream in SCD may impact hemodynamics and the functionality of other blood cells, i.e., white blood cells (WBCs) and platelets, and the downstream contribution to disease manifestation beyond the occlusion of the microvasculature, which is primarily attributed to the i-sRBCs that cause significant physical damage to vital organs, including the spleen, liver, and lungs, when traveling through the body. The goal of this project is to develop and use a unique combination of experimental tools to quantify r-sRBC rigidity in SCD and to systematically explore how this rigidity affects the spatial distribution and the dynamic behavior of white blood cells (WBCs) and platelets as it relates to disease symptoms, such as infection rate and pain crisis. The research plan is designed to test the central hypothesis that the r-sRBCs in SCD patient blood alter the margination of WBC and platelets, impacting their ability to respond to disease symptoms in SCD. The Research Plan is organized under three objectives. The FIRST OBJECTIVE is to characterize the stiffness of the diseased RBC population in SCD patient blood via ektacytometry with a model SCD blood having artificially rigidified RBCs used for calibration. The SECOND OBJECTIVE is to evaluate how WBC and platelet adhesion to the blood vessel wall changes with varying level of RBC stiffness in SCD and the downstream impact on disease presentation. The THIRD OBJECTIVE is to determine the impact of diluting the stiff RBC fractions, as would occur during blood transfusion, on the ability of WBCs and platelets to adhere, using flow adhesion models.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.